19-nortestosterone phenyl alkanoates



United State p 1I9-NORTESTOSTERONEVPH'ENYL ALKANOATES No Drawing.Application August 12, 1954 Serial No. 449,502

7 Claims. (Cl. 260397.4)

The present invention pertains to'steroid compounds 16 related totestosterone and is more particularly concerned with novel19-nortestosterone l7-phenylalkanoates wherein the alkanoate biradicalcontains fromv two to three. carbon atoms, inclusive, and the 3-enolacylates thereof wherein an acylate radical is of the formula AcO, Acbeing the acyl radical of a hydrocarbon monocarboxylic acid containingfrom two to nine carbon atoms, -in-' elusive. 1 v

This application is a continuation-in-part of our copending applicationSerial No. 349,096, filed April '15, 1953. v v

In the present invention, the 19-nortestosterone 17- phenylalkanoate'smay be represented by the formula:

. cottonseed'oil, subcutaneously to rats, castrated at a body wherein nis an integer from one to two, inclusive, and AcO is an acylate group,Ac being the acyl radical of a hydrocarbon monocarboxylic acidcontaining from two to nine carbon atoms, inclusive. It is an object ofthis invention to provide novel 19- nortestosterone 17-phenyla1kanoates.and 3-enol ,acylates thereof of-the above formulas, which. have very'high anabolic activity and an exceedingly highvratio. of'anabolicactivity to androgenic activity. Therefore thecom pounds of the presentinvention are. useful as anabolic agents of high potency having verylittle androgenic side effects. Other'objects and uses will be apparentto: one skilled in the art.

It has been shown inour copending application Serial No. 349,096, nowPatent No. 2,798,879; issuedluly 9,, 1957, that certainl9-nortestosterone l7-acylates and 3- enol acylates thereof arecompounds having high and prolonged anabolic activity and a high ratioof anabolic 210- tivity to androgenic activity (e. g., A-C, Table 1):.Now it has been found'that the 19-nortestoster0ne 17-phenyla race w:

ice

alkanoates and 3-eno1 acylates thereof of'the present invention aremarkedly superior to other 19-nortestosterone 17-acylates and 3-enolacylates thereof (e. g., D, Table I), and also to testosterone17,-pheny1acetate (B, Table I). For example, l9-nortestosterone17-phenylacetate has markedly greater anabolic activity than the other19-- nortestosterone esters in Table I,' and it has about ten times theanabolic activity-of testosterone 17-pheny1acetate. Likewise the ratioof anabolic activity to androgenie activity of 19-nortestosterone17-phenylacetate is almost twice that of the most active other19-nortestosterone acylate, and its ratio is more than 18 times that oftestosterone l7-phenylacetate. Moreover, the amount of19-nortestosterone 17-phenylacetate required to obtain I a particularanabolic effect is considerably less than that of other19-nortestosterone esters, and to obtain an equal anabolic effect withtestosterone l7-phenylacetate more 'than'eight times the amount isrequired.

TABLEv I Potency Ratio of Relative Test Compound Weights of toTestosterone Ratio of Test Com- Iest Compound 19- Tor- PropionateAnabolic pounds testosterone 17-acy1ate to Andro- Producing genie EqualAndro- Anabolic Activity Anabolic genie Activity Efiects Activity17-propi0nate 0.4 2.6 6.3 0.4 17-(B-cyclopentylpropionate) 0.2 2. 1 9. 60. 5 17-trimethylacetate-.. 0.02 0.2 9.0 5. 5 17-phenylacetate 0.2 3.718.5 0.3 Testrosterone 17- phenylacetate 0. 4 0. 4 l. 0 2. 5Testosterone proplonate (Standard) 1.0 1.0 1.0 1.0

'In Table I, Potency ratio of test compound to testosterone propionatewa determined by the method of Irwin [Supplements to the Journal of theRoyal Statistical Society, vol. IV, No. 1, page 1 (1937)] fromdose-response curves, using one curve for each type of activity of eachtest compound, the amount of activity, or respouse, being plottedagainst the amount, or dose, of test compound used for each. of severaldosage levels. The experimental data used: for plotting thedose-response curves was obtained by administering the test compounds inequal daily doses, each contained in 0.1 milliliter of weight of 40 to45 grams, for 21 days beginning on the day following, castration, usingat least five rats for each dosage level of each compound; and, atautopsy on the day'following' the last injection, determining the bodyWeight; seminal vesicle. weight, and levator ani muscle acylate thereofof the present invention are prepared by acylation of 19-nortestosteroneusing an acyla'ting agent such as, for example, an acid, acid anhydride,acid halide, ester of an acid with a lower alcohol, a ketene, etc., to

convert the alcoholic hydroxy group to an ester and,

when desired, the ketone group to an enol ester. In general a basiccatalyst is employed to obtain 17-acylation, while an acid catalyst isnormally used to obtain 3-eno1 acylation, or 3-enol acylation and17-acylation. The 19-nortestosterone l7-phenylalkanoates also areobtamed by partial hydrolysis of the 3.-enol acylates of 19-nortestosterone l7-phenyl'alkanoates.-

The following examples are illustrative of the-processes Example1.19-n0rtesto:s'ter0ne 17-phenylacetate An ice-cold solution of 1.5grams of 19-nortestosterone and 1.5 milliliters of dry pyridine in tenmilliliters of dry benzene is prepared and a solution of phenylacetylchloride (0.9 milliliter) in five milliliters of dry benzene is addeddropwise over a period of about two minutes with stirring. The resultingmixture is allowed to stand overnight under an atmosphere of nitrogenand then washed successively With cold 5 percent aqueous hydrochloricacid solution, cold 2.5 percent aqueous sodium hydroxide solution, andwater. After drying over anhydrous sodium sulfate, the solvent isevaporated to give an almost colorless oil (1.95 grams).Recrystallization from petroleum ether (boiling at to degreescentigrade) gives white crystals of l9-nortestosterone l7-phenylacetate,melting point 72 to 76 degrees centigrade.

Analysis.-Calculated for C H O C, 79.55; H, 8.22. Found: C, 79.74; H,8.52.

Heating the 19-nortestosterone l7-phenylacetate under reflux withphenylacetyl chloride and a catalytic amount of paratoluenesulfonicacid, using toluene as a solvent,

for a period of several hours, cooling and diluting the resultingsolution with cold water, and filtering the solid obtained, provides the3-enol phenylacetate of 19-nortestosterone 17- phenylacetate.19-nortestosterone is converted to the 3-enol phenylacetate of19-nortestosterone 17-phenylacetate in one step by usingl9-nortestosterone 1.5 milliliters of fi-phenylpropionyl chloride infive milliliters of dry benzene is added dropwise. The reaction isconducted as in Example 1, and the oil obtained is crystallized frommethanol to give l9-nortestosterone l7- (fi-phenylpropionate),melting-point 91 to 92.5 degrees centigrade.

19'-nortestosterone l7-(B-phenylpropionate) is converted to a 3-enolacylate such as, for example, the 3-er1ol acetate, or the 3-enolfi-cyclopentylpropionate, in the same manner as shown for thepreparation of the 3-enol acylatc of l9-nortestosterone l7-phenylacetatein Example 1. Other 3-e nol acylates of 19-nortestosteronel7-(;8-phenylpropionate) include the 3-enol propionate, formate,butyrate, isobutyrate, pentanoate, hexanoate, heptanoate, octanoate,fi-phenylpropionate, and like 3-enol acylates.

Example 3.19-n0rtest0ster0ne 1 7 a-phenylpropionate) By reaction ofl9-nortestosterone and a-phenylpropionyl chloride, following the methodof Example 1, l9-

nortestosterone l7-(a-phenylprop1onate) is produced. 3-

enol acylates of 19-nortestosterone l7-(a-phenylpropionate), prepared asin Examples 1 and 2, include the 3-cnol propionate, acetate, benzoate,phenylacetate, and like 3-enol acylates of l9-nortestosteronel7-(a-phenylpropionate). Partial hydrolysis of these compounds pro vide19-nortestosterone 17-(a-phenylpropionate).'

Table II gives melting points, analytical data, and the acylating agentemployed, of other l9-nortestosterone 17- acylates, and 3-enol acylatesthereof, prepared according to the procedures of Examples 1 through 3.

TABLE II Analysis l7Acylate of 19-N0rtestosterone M. P. O.) AcylatingAgent Calc'd Found Acetoacetate waxy solid g g: Acid ethyl ester10-Hendecenoate. 01L acid chloride. Formate l05 nn g 75: 74 free acid.Acid glutar 165-17 55 acid anhydl'ide' Glutarate 203215 Do. mums, 87.90gyg; gg 3g and wondei-Valerate oil gfggg 51% n-Heptanoateoil. Do.Diphenylacetate glass 33 3131 M an; in: Ethoxy 75-85 Do.p-Trlfluoro-acetamido-phenylacetate.-. 178-185 fret? agriltll1 (311.1%1;)rifiuoroacec y 1 e C :67. 74 67. 96 phosgene. Chloroiormate -85 H: 7.48 7.81 C1110. 53 10. 17 gfgtrophenzl acetate acig chllglirglea uornar pa. n 5 aci a y ti o.

Propionate, 3-enol propionate 112-116 g: %;?$g{ gg; Butyrate, 3-enolbutyrate acid chloride.

Example 2.-19-nortest0sterone 17-(fl-phenylpropionate) A solution of 2.5grams of l9-nortestosterone and 2.5 milliliters of dry pyridine in tenmilliliters of dry benzene is prepared and, following the procedure ofExample 1,

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. A compound selected from the group consisting of l9-nortestosterone17-phenylalkanoate wherein the alkanoate biradical contains from two tothree carbon atoms. inclusive, and the 3enol acylate thereof wherein anacylate radical is of the formula AcO, Ac being the acyl radical of ahydrocarbon monocarhoxylic acid containing from two to nine carbonatoms, inclusive.

2. 19- nortestosterone 17-phenylalkanoate wherein the 4.19-nortestosterone 17-phenylacetate. 5. 19-nortestosterone17-phenylpropionate. 6. 19-nortestosterone l7-(a-phenylpropionate). 7.19-nortestosterone (17-(B-phenylpropionate).

References Cited in the file of this patent UNITED STATES PATENTS2,698,855 Hicks Jan. 4, 1955

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 19-NORTESTOSTERONE17-PHENYLALKANOATE WHEREIN THE ALKANOATE BIRADICAL CONTAINS FROM TWO TOTHREE CARBON ATOMS, INCLUSIVE, AND THE 3-ENOL ACYLATE THEREOF WHEREIN ANACYLATE RADICAL IS OF THE FORMULA ACO, AC BEING THE ACYL RADICAL OF AHYDROCARBON MONOCARBOXYLIC ACID CONTAINING FROM TWO TO NINE CARBONATOMS, INCLUSIVE.